Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - indomethacin (unii: xxe1cet956) (indomethacin - unii:xxe1cet956) - indomethacin extended-release capsules are indicated for: indomethacin extended-release capsules are contraindicated in the following patients: risk summary use of nsaids, including indomethacin extended-release capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of indomethacin extended-release capsules use between about 20 and 30 weeks of gestation, and avoid indomethacin extended-release capsules use at about 30 weeks of gestation and later in pregnancy (see clinical considerations, data ). data from observational studies regarding other potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. in animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (mrhd, 200 mg). in published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the mrhd. when rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the mrhd, respectively [see data ]. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including indomethacin extended-release capsules, can cause premature closure of the fetal ductus arteriosus (see data ). oligohydramnios/neonatal renal impairment if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if indomethacin extended-release capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue indomethacin extended-release capsules and follow up according to clinical practice (see data ). labor or delivery there are no studies on the effects of indomethacin extended-release capsules during labor or delivery. in animal studies, nsaids, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data human data premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal data reproductive studies were conducted in mice and rats at dosages of 0.5, 1, 2 and 4 mg/kg/day. except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the mrhd on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. other studies in mice reported in the literature using higher doses (5 mg/kg/day to 15 mg/kg/day, 0.1 to 0.4 times mrhd on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. in rats and mice, maternal indomethacin administration of 4 mg/kg/day (0.2 times and 0.1 times the mrhd on a mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the mrhd on a mg/m2 basis). administration of 0.5 mg/kg/day or 4 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. risk summary based on available published clinical data, indomethacin may be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin extended-release capsules and any potential adverse effects on the breastfed infant from the indomethacin extended-release capsules or from the underlying maternal condition. data in one study, levels of indomethacin in breast milk were below the sensitivity of the assay (< 20 mcg/l) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 mg/kg to 4.29 mg/kg daily) in the postpartum period. based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. in another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. the estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/ kg/day assuming breast milk intake of 150 ml/kg/day. this is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including indomethacin extended-release capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including indomethacin extended-release capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility. safety and effectiveness in pediatric patients 14 years of age and younger has not been established. indomethacin extended-release capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. in experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin immediate-release capsules, side effects in pediatric patients were comparable to those reported in adults. experience in pediatric patients has been confined to the use of indomethacin immediate-release capsules. if a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. there have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. if indomethacin treatment is instituted, a suggested starting dose is 1 mg/kg/day to 2 mg/kg/day given in divided doses. maximum daily dosage should not exceed 3 mg/kg/day or 150 mg/day to 200 mg/day, whichever is less. limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 mg/day to 200 mg/day, whichever is less. as symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see warnings and precautions (5.1, 5.2, 5.3, 5.6, 5.14) ]. indomethacin may cause confusion or rarely, psychosis [see adverse reactions (6.1) ]; physicians should remain alert to the possibility of such adverse effects in the elderly indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see clinical pharmacology (12.3 )].

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - levofloxacin (unii: 6gnt3y5lmf) (levofloxacin anhydrous - unii:rix4e89y14) - levofloxacin tablets are indicated in adult patients for the treatment of nosocomial pneumonia due to methicillin-susceptible staphylococcus aureus , pseudomonas aeruginosa , serratia marcescens , escherichia coli , klebsiella pneumoniae , haemophilus influenzae , or streptococcus pneumoniae . adjunctive therapy should be used as clinically indicated. where pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended [see clinical studies (14.1)] . levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia due to methicillin-susceptible staphylococcus aureus , streptococcus pneumoniae (including multi-drug-resistant streptococcus pneumoniae [mdrsp]), haemophilus influenzae , haemophilus parainfluenzae , klebsiella pneumoniae , moraxella catarrhalis , chlamydophila pneumoniae , legionella pneumophila , or mycoplasma pneumoniae [see dosage and administration (2.1) and clinical studies (14.2)] .

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - deferasirox (unii: v8g4mof2v9) (deferasirox - unii:v8g4mof2v9) - deferasirox tablets for oral suspension are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. deferasirox tablets for oral suspension are indicated for the treatment of chronic iron overload in patients 10 years of age and older with non- transfusion-dependent thalassemia (ntdt) syndromes and with a liver iron concentration (lic) of at least 5 milligrams of iron per gram of liver dry weight (mg fe/g dw) and a serum ferritin greater than 300 mcg/l. the safety and efficacy of deferasirox when administered with other iron chelation therapy have not been established. deferasirox tablets for oral suspension are contraindicated in patients with: known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension [see warnings and precautions ( error! hyperlink reference not valid. ), adverse reactions ( error! hyperlink reference not valid. )] . risk summary there are no studies with the use of deferasirox in pregnant women to inform drug-associated risks. administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on an mg/m2 basis. no fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m2 basis. deferasirox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. the background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. however, the background risk in the u.s. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. data animal data in embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (mrhd) on an mg/m2 basis). these doses resulted in maternal toxicity but no fetal harm was observed. in a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1 times the mrhd on an mg/m2 basis). maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1 times the mrhd on a mg/m2 basis) and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the mrhd on a mg/m2 basis). risk summary no data are available regarding the presence of deferasirox or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. deferasirox and its metabolites were excreted in rat milk. because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in a breastfeeding child from deferasirox and its metabolites, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother. contraception counsel patients to use non-hormonal method(s) of contraception since deferasirox can render hormonal contraceptives ineffective [see drug interactions ( error! hyperlink reference not valid. )] . transfusional iron overload the safety and effectiveness of deferasirox have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload [see dosage and administration (2.1)] . safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload. pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias. seventy percent of these patients had beta-thalassemia [see indications and usage (1), dosage and administration (2.1), clinical studies (14)]. in those clinical studies, 173 children (ages 2 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox. a trial conducted in treatment-naïve pediatric patients, 2 to < 18 years of age with transfusional iron overload (nct02435212) did not provide additional relevant information about the safety or effectiveness of the deferasirox granules dosage form (jadenu sprinkle) compared to the deferasirox oral tablets for suspension dosage form. iron overload in non-transfusion-dependent thalassemia syndromes the safety and effectiveness of deferasirox have been established in patients 10 years of age and older for the treatment of chronic iron overload with non-transfusion-dependent thalassemia (ntdt) syndromes [see dosage and administration (2.2)] . safety and effectiveness have not been established in patients less than 10 years of age with chronic iron overload in ntdt syndromes. pediatric approval for treatment of ntdt syndromes with liver iron (fe) concentration (lic) of at least 5 mg fe per gram of dry weight and a serum ferritin greater than 300 mcg/l was based on 16 pediatric patients treated with deferasirox therapy (10 years to less than 16 years of age) with chronic iron overload and ntdt. use of deferasirox in these age groups is supported by evidence from adequate and well-controlled studies of deferasirox in adult and pediatric patients [see indications and usage (1.2), dosage and administration (2.2), clinical studies (14)]. in general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs. acute kidney injury, and acute liver injury and failure has occurred in pediatric patients. in a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. higher rates of renal adverse reactions have been identified among pediatric patients receiving deferasirox doses greater than 25 mg/kg/day when their serum ferritin values were less than 1,000 mcg/l [see dosage and administration ( error! hyperlink reference not valid. ), warnings and precautions ( error! hyperlink reference not valid. , error! hyperlink reference not valid. ), adverse reactions ( error! hyperlink reference not valid. , error! hyperlink reference not valid. )] . monitoring recommendations for pediatric patients with transfusional iron overload and ntdt it is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimize the risk of overchelation [see warnings and precautions (5.6)]. monitor renal function by estimating gfr using an egfr prediction equation appropriate for pediatric patients and evaluate renal tubular function. monitor renal function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. use the minimum effective dose [see warnings and precautions ( error! hyperlink reference not valid. )]. interrupt deferasirox in pediatric patients with transfusional iron overload and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. evaluate the risk benefit profile of continued deferasirox use in the setting of decreased renal function. avoid use of other nephrotoxic drugs [see dosage and administration ( error! hyperlink reference not valid. ), warnings and precautions ( error! hyperlink reference not valid. )]. juvenile animal toxicity data renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. in a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum day 7 through 70, which equates to a human age range of term neonate through adolescence. increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m2 approximately 0.4 times the recommended dose of 20 mg/kg/day. a higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals. four hundred thirty-one (431) patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting. two hundred twenty-five (225) of these patients were between 65 and 75 years of age while 206 were greater than or equal to 75 years of age. the majority of these patients had myelodysplastic syndrome (mds) (n = 393). in these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. in elderly patients, including those with mds, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox therapy. deferasirox is contraindicated in patients with egfr less than 40 ml/min/1.73 m2 [see contraindications (4)]. for patients with renal impairment (egfr 40 to 60 ml/min/1.73 m2 ), reduce the starting dose by 50% [see dosage and administration (2.4)]. exercise caution in pediatric patients with egfr between 40 and 60 ml/minute/1.73 m2 [see dosage and administration (2.4)]. if treatment is needed, use the minimum effective dose with enhanced monitoring of glomerular and renal tubular function. individualize dose titration based on improvement in renal injury [see dosage and administration (2.4, 2.5)]. deferasirox can cause glomerular dysfunction, renal tubular toxicity, or both, and can result in acute renal failure. monitor all patients closely for changes in egfr and renal tubular dysfunction during deferasirox treatment. if either develops, consider dose reduction, interruption or discontinuation of deferasirox until glomerular or renal tubular function returns to baseline [see dosage and administration (2.4, 2.5), warnings and precautions (5.1)]. avoid the use of deferasirox in patients with severe (child-pugh c) hepatic impairment. for patients with moderate (child-pugh b) hepatic impairment, the starting dose should be reduced by 50%. closely monitor patients with mild (child-pugh a) or moderate (child-pugh b) hepatic impairment for efficacy and adverse reactions that may require dose titration [see dosage and administration (2.4), warnings and precautions (5.2)].

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark therapeutics inc., usa - citalopram hydrobromide (unii: i1e9d14f36) (citalopram - unii:0dhu5b8d6v) - citalopram tablets are indicated for the treatment of major depressive disorder (mdd) in adults [see clinical studies (14)] . citalopram tablets are contraindicated in patients: pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants. risk summary based on data from published observational studies, exposure to ssris, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see warnings and precautions ( 5.4) and clinical considerations] . available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark generics inc., usa - citalopram hydrobromide (unii: i1e9d14f36) (citalopram - unii:0dhu5b8d6v) - citalopram hydrobromide 10 mg - citalopram tablets usp are indicated for the treatment of depression. the efficacy of citalopram tablets usp in the treatment of depression was established in 4-6 week; controlled trials of outpatients whose diagnosis corresponded most closely to the dsm-iii and dsm-iii-r category of major depressive disorder (see clinical pharmacology ). a major depressive episode (dsm-iv) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. the antidepressant action of citalopram tablets usp in hospitalized depressed patients has not been adequately studied. the

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - lamotrigine (unii: u3h27498ks) (lamotrigine - unii:u3h27498ks) - lamotrigine 25 mg - lamotrigine is indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: lamotrigine is indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (aed). safety and effectiveness of lamotrigine have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from aeds other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant aeds. lamotrigine is indicated for the maintenance treatment of bipolar i disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in adults (aged 18 years and older) treated for acute mood episodes with standard therapy [see clinical studies (14.1)] . limitations of use treatment of acute manic or mixed episod

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - lamotrigine (unii: u3h27498ks) (lamotrigine - unii:u3h27498ks) - lamotrigine 5 mg - lamotrigine tablets for oral suspension (chewable, dispersible tablets) are indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older: lamotrigine tablets for oral suspension (chewable, dispersible tablets) are indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (aed). safety and effectiveness of lamotrigine tablets for oral suspension (chewable, dispersible tablets) have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from aeds other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant aeds. lamotrigine tablets for oral suspension (chewable, dispersible tablets) are indicated for the maintenance treatment of bipolar i disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy [see clinical studies (14.2)] . limitations of use treatment of acute manic or mixed episodes is not recommended. effectiveness of lamotrigine tablets for oral suspension (chewable, dispersible tablets) in the acute treatment of mood episodes has not been established. lamotrigine is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see boxed warning, warnings and precautions (5.1, 5.3)] . pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aeds, including lamotrigine, during pregnancy. encourage women who are taking lamotrigine during pregnancy to enroll in the north american antiepileptic drug (naaed) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. risk summary data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population (see data) . the majority of lamotrigine pregnancy exposure data are from women with epilepsy. in animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically. lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans (see data) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations as with other aeds, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. there have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery. dose adjustments may be necessary to maintain clinical response. data human data: data from several international pregnancy registries have not shown an increased risk for malformations overall. the international lamotrigine pregnancy registry reported major congenital malformations in 2.2% (95% ci: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy. the naaed pregnancy registry reported major congenital malformations among 2.0% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester. eurap, a large international pregnancy registry focused outside of north america, reported major birth defects in 2.9% (95% ci: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester. the frequency of major congenital malformations was similar to estimates from the general population. the naaed pregnancy registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% ci: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls. this finding has not been observed in other large international pregnancy registries. furthermore, a case-control study based on 21 congenital anomaly registries covering over 10 million births in europe reported an adjusted odds ratio for isolated oral clefts with lamotrigine exposure of 1.45 (95% ci: 0.8, 2.63). several meta-analyses have not reported an increased risk of major congenital malformations following lamotrigine exposure in pregnancy compared with healthy and disease-matched controls. no patterns of specific malformation types were observed. the same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay. although there are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure, differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions that can be drawn. animal data: when lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. the no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m2 ) basis. in a study in which pregnant rats were administered lamotrigine (oral doses of 0, 5, or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, neurobehavioral abnormalities were observed in exposed offspring at both doses. the lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. maternal toxicity was observed at the higher dose tested. when pregnant rats were administered lamotrigine (oral doses of 0, 5, 10, or 20 mg/kg) during the latter part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen at all doses. the lowest effect dose for pre- and post-natal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. maternal toxicity was observed at the 2 highest doses tested. when administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m2 basis. risk summary lamotrigine is present in milk from lactating women taking lamotrigine tablets (see data) . neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but is not reduced after delivery to the pre-pregnancy dosage. glucuronidation is required for drug clearance. glucuronidation capacity is immature in the infant and this may also contribute to the level of lamotrigine exposure. events including rash, apnea, drowsiness, poor sucking, and poor weight gain (requiring hospitalization in some cases) have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. no data are available on the effects of the drug on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lamotrigine and any potential adverse effects on the breastfed infant from lamotrigine or from the underlying maternal condition. clinical considerations human milk-fed infants should be closely monitored for adverse events resulting from lamotrigine. measurement of infant serum levels should be performed to rule out toxicity if concerns arise. human milk-feeding should be discontinued in infants with lamotrigine toxicity. data data from multiple small studies indicate that lamotrigine plasma levels in nursing infants have been reported to be as high as 50% of maternal plasma concentrations. epilepsy lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of lennox-gastaut syndrome, and pgtc seizures. safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged 1 to 24 months). lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%). infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. respiratory adverse reactions included nasal congestion, cough, and apnea. bipolar disorder safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by dsm-iv-tr. in the randomized phase of the trial, adverse reactions that occurred in at least 5% of patients taking lamotrigine (n = 87) and were twice as common compared with patients taking placebo (n = 86) were influenza (lamotrigine 8%, placebo 2%), oropharyngeal pain (lamotrigine 8%, placebo 2%), vomiting (lamotrigine 6%, placebo 2%), contact dermatitis (lamotrigine 5%, placebo 2%), upper abdominal pain (lamotrigine 5%, placebo 1%), and suicidal ideation (lamotrigine 5%, placebo 0%). juvenile animal data in a juvenile animal study in which lamotrigine (oral doses of 0, 5, 15, or 30 mg/kg) was administered to young rats from postnatal day 7 to 62, decreased viability and growth were seen at the highest dose tested and long-term neurobehavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. the no-effect dose for adverse developmental effects in juvenile animals is less than the human dose of 400 mg/day on a mg/m2 basis. clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. experience in patients with hepatic impairment is limited. based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment [see clinical pharmacology (12.3)] , the following general recommendations can be made. no dosage adjustment is needed in patients with mild liver impairment. initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. escalation and maintenance doses may be adjusted according to clinical response [see dosage and administration (2.1)]. lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. in a small study comparing a single dose of lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of lamotrigine was approximately twice as long in the subjects with chronic renal failure [see clinical pharmacology (12.3)] . initial doses of lamotrigine should be based on patients’ aed regimens; reduced maintenance doses may be effective for patients with significant renal impairment. few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. because there is inadequate experience in this population, lamotrigine should be used with caution in these patients [see dosage and administration (2.1)] .

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - atomoxetine hydrochloride (unii: 57wvb6i2w0) (atomoxetine - unii:asw034s0b8) - atomoxetine 10 mg - pregnancy exposure registry there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to adhd medications, including atomoxetine, during pregnancy. healthcare providers are encouraged to register patients by calling the national pregnancy registry for adhd medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . risk summary available published studies with atomoxetine use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. some animal reproduction studies of atomoxetine had adverse developmental outcomes. one of 3 studies in pregnant rabbits dosed during organogenesis resulted in decreased live fetuses and an increase in early resorptions, as well as slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery. these effects were observed at plasma levels (auc) 3 times and 0.4 times the human plasma levels in e

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - raloxifene hydrochloride (unii: 4f86w47br6) (raloxifene - unii:yx9162eo3i) - raloxifene hydrochloride 60 mg - raloxifene hydrochloride tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women [see clinical studies (14.1, 14.2)]. raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis [see clinical studies (14.3)]. raloxifene hydrochloride tablets are indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer [see clinical studies (14.4)] . the effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years [see clinical studies (14.4)]. twenty-seven percent of the participants received drug for 5 years. the long-term effects and the recommended length of treatment are not known. high risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (lcis) or atypic

Ameerika Ühendriigid - inglise - NLM (National Library of Medicine)

glenmark pharmaceuticals inc., usa - meloxicam (unii: vg2qf83cgl) (meloxicam - unii:vg2qf83cgl) - meloxicam 7.5 mg - meloxicam tablets are indicated for relief of the signs and symptoms of osteoarthritis [see clinical studies (14.1)] . meloxicam tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis [see clinical studies (14.1)] . meloxicam tablets are indicated for relief of the signs and symptoms of pauciarticular or polyarticular course juvenile rheumatoid arthritis in patients who weigh ≥ 60 kg [see dosage and administration (2.4) and clinical studies (14.2)] . meloxicam tablets are contraindicated in the following patients: risk summary use of nsaids, including meloxicam, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. because of these risks, limit dose and duration of meloxicam use between about 20 and 30 weeks of gestation, and avoid meloxicam use at about 30 weeks of gestation and later in pregnancy (see clinical considerations, data) . premature closure of fetal ductus arteriosus use of nsaids, including meloxicam, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. data from observational studies regarding potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. in animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.65- and 6.5-times the maximum recommended human dose (mrhd) of meloxicam. increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 78-times the mrhd. in pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.08-times mrhd of meloxicam. no teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2.6 and 26-times the mrhd [see data] . based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including meloxicam, can cause premature closure of the fetal ductus arteriosus (see data) . oligohydramnios/neonatal renal impairment: if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if meloxicam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue meloxicam and follow up according to clinical practice (see data) . labor or delivery there are no studies on the effects of meloxicam during labor or delivery. in animal studies, nsaids, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data human data premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain. animal data meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the mrhd of 15 mg of meloxicam based on bsa comparison). administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (78-fold greater than the mrhd based on bsa comparison). the no effect level was 20 mg/kg/day (26-fold greater than the mrhd based on bsa conversion). in rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65-and 6.5-fold greater, respectively, than the mrhd based on bsa comparison) when administered throughout organogenesis. oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times mrhd based on bsa comparison). risk summary there are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for meloxicam and any potential adverse effects on the breastfed infant from the meloxicam or from the underlying maternal condition. data animal data meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma. infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including meloxicam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including meloxicam, in women who have difficulties conceiving or who are undergoing investigation of infertility. the safety and effectiveness of meloxicam in pediatric jra patients from 2 to 17 years of age has been evaluated in three clinical trials [see dosage and administration (2.3), adverse reactions (6.1) and clinical studies (14.2)] . elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see warnings and precautions (5.1, 5.2, 5.3, 5.6, 5.14)]. no dose adjustment is necessary in patients with mild to moderate hepatic impairment. patients with severe hepatic impairment have not been adequately studied. since meloxicam is significantly metabolized in the liver and hepatotoxicity may occur, use meloxicam with caution in patients with hepatic impairment [see warnings and precautions (5.3) and clinical pharmacology (12.3)]. no dose adjustment is necessary in patients with mild to moderate renal impairment. patients with severe renal impairment have not been studied. the use of meloxicam in subjects with severe renal impairment is not recommended. in patients on hemodialysis, meloxicam should not exceed 7.5 mg per day. meloxicam is not dialyzable [see dosage and administration (2.1) and clinical pharmacology (12.3)].